This is part two of a two-part interview discussing highlights from CROI 2010 related to antiretroviral therapy for HIV-infected patients. Part one focuses on antiretrovirals in development; part two focuses on already-approved antiretrovirals, the question of when to initiate antiretroviral therapy and the evolution of the CROI meeting itself. You can use the table of contents below to quickly jump from section to section.

Improving Our Understanding of Approved Antiretrovirals

Myles Helfand: From drugs in development, let's move on to drugs that are already on the market. What kind of research was presented here at CROI regarding recent efforts to improve existing treatment options for patients?

ACTG 5202: Four Drugs Enter

Joel Gallant: Probably the most important one was the eagerly awaited results of ACTG 5202. This may have been the most confusing presentation at CROI, not because the presenter did a bad job but because, again, they were forced to combine a lot of data into a 10-minute period. This was a study that looked at two things. It looked at Epzicom [abacavir/lamivudine, ABC/3TC, Kivexa] versus Truvada [tenofovir/emtricitabine, TDF/FTC], and it looked at Sustiva [efavirenz, EFV, Stocrin] versus boosted Reyataz [atazanavir, ATV]. Since there were two comparisons, there are four arms: You have Truvada/Sustiva, Truvada/Reyataz, Epzicom/Sustiva and Epzicom/Reyataz. It's a complicated study design.

We had already heard, in Mexico City in 2008, the results of an interim analysis, where the DSMB [Data Safety Monitoring Board] recommended that the patients with a viral load of above 100,000 copies/mL be unblinded as to their nucleoside assignment, because the Epzicom was underperforming. There was a higher rate of virologic failure in that group of patients with high viral loads, and it was suggested that they switch over to Truvada. That's the last we heard, and nobody understood why that had happened. We were all waiting to see the final results.

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As you could imagine, in any study comparing four different regimens, with the size of the study, there are going to be a lot of different nuances. The bottom line for me is that this was probably, I think, the first clinical trial that showed that a boosted protease inhibitor [PI] could be as effective as Sustiva. So, in terms of virologic efficacy, boosted Reyataz and Sustiva were pretty much the same. That was true, whether you looked at [whether either drug was taken with] Epzicom or Truvada.

The other thing that I thought was interesting: I think most people assume that because Epzicom didn't do as well as Truvada in the high viral loads, we would see some inkling of that in the lower viral loads -- that we would say, "Well, maybe the differences weren't as big, but Epzicom would still not be as good as Truvada at low viral loads." In fact, that really wasn't true. At the low viral loads, you couldn't see any sign of that earlier failure that we had seen at the high viral loads, making it still very puzzling why we saw that in the earlier analysis.

But there were some differences, mostly favoring Truvada, and that had to do with safety and tolerability. If you looked at the time it took before you got to a significant safety event, if you were taking Epzicom with Sustiva you were more likely to develop one of those events than if you were taking Truvada/Sustiva. It didn't seem to affect the ones who were on Reyataz.

There was also a shorter time to treatment modification if you were on Epzicom, with either Sustiva or Reyataz. Now, a lot of that was probably because of [abacavir (ABC, Ziagen)] hypersensitivity: They weren't doing HLA-B*5701 screening in this study. So you could argue that kind of a difference wouldn't apply today, where we screen people and they don't develop hypersensitivity reactions.

And then, finally, there were greater lipid changes with Epzicom versus Truvada. And there were greater lipid changes with Sustiva. So if you were on Epzicom and Sustiva, it was kind of a double hit, because you had the two drugs that caused the most lipid changes.

On the other hand, the lipid changes that were seen were not affecting the cholesterol HDL [high-density lipoprotein] ratios. So some would argue that, even though there are differences, it's probably of marginal clinical significance.

There are all sorts of other comparisons we could look at, but it gets pretty tricky. I guess one that I should mention, too, is that if you did fail on Sustiva, you were more likely to develop resistance than if you failed on Reyataz. And that's not surprising; we saw that in [ACTG study] 5142, when Sustiva was compared with Kaletra [lopinavir/ritonavir, LPV/r].

So, lots of little nuances here, but I think there are at least some conclusions we could draw from this.

How to Choose Between First-Line Regimens

Myles Helfand: This is a dizzying number of different conclusions. Some of them are potentially conflicting. Adverse events on efavirenz versus atazanavir; high viral load being worse for Epzicom than for Truvada, but not so much at lower viral load levels.

We've got these four or five different regimens that could potentially work really well for first-line therapy. Do you need to literally go to a chalkboard and work out a chart where you're laying out, "OK, so these are all the pluses of this regimen; these are all the minuses"; and then weigh positives and negatives with many different regimens before you make a decision? Or can we somehow simplify this?

Joel Gallant: I think that's what we have guidelines for. Maybe I have a bias, in the sense that I'm on the [U.S. Department of Health and Human Services] guidelines panel [for the treatment of HIV-infected adults and adolescents]. But I think the guidelines panel does this job for you. They sort out the data, and they come up with some recommendations that I think are quite reasonable.

Obviously, the panel will need to go and look at 5202, and a number of the other studies presented at CROI, to make sure that changes aren't required. But I actually think, personally, that the list is a pretty good list right now, for preferred regimens, and that the 5202 results support the current list.

So the current list of preferred regimens is: Truvada plus either boosted Reyataz, boosted Prezista [darunavir, TMC114], Isentress [raltegravir, RAL] or Sustiva (in which case it's Atripla [efavirenz/tenofovir/emtricitabine, EFV/TDF/FTC]). Those four regimens, I think, are the right ones to reach for. But they won't be the right ones for all patients, and that's where you go to the alternative list, which is also a good list of regimens.

"Preferred" vs. "Alternative": What's the Difference?

Myles Helfand: That's actually maybe a point worth emphasizing: The word "alternative" can be, I think -- and maybe has been -- misconstrued by portions of the clinical community to mean, well, maybe you should avoid these drugs. But it seems like what you're saying is, if the preferred drugs work really well, the alternative ones work really well, too; they may just not be the greatest ones to use, because you've got better.

Joel Gallant: Yes. I think the point that the guidelines make is very important. It says the "alternative" regimens may be preferred for some patients. So, for example, if you have a patient with kidney problems, then none of those preferred regimens may be the right choice [due to tenofovir's association with nephrotoxicity], and an Epzicom-based regimen may be preferred for that patient. It doesn't mean you're using a bad regimen. It's kind of saying, if all else is equal, you would pick a preferred regimen; if there is no reason not to pick a preferred regimen, you would pick one of them. But a pregnant woman should be on Kaletra [instead of efavirenz], for example. Somebody with kidney disease should not be on tenofovir. So there are lots of reasons to go to the alternative list. And they are perfectly acceptable regimens. Most of them have shown good efficacy, and it's just an issue of maybe some tolerability differences, and things like that.

Myles Helfand: So, moral of the story, as the biased representative: study the guidelines.

Joel Gallant: Yes, absolutely. And I would say, too, that when you look at the guidelines, don't just look at the tables. People tend to think of the guidelines as a few tables that tell them what to do. But, boy, things are getting complex, and especially the "when to start" question -- where, within the guidelines panel, there are differences of opinion. If you read the text, I think you really will learn a lot, and get a better sense for the nuances and subtleties of what we're recommending.

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